1-(3-cyanophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methylpyrazole | 209960-79-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 1-(3-cyanophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methylpyrazole
• 英文别名: 1-(3-cyanophenyl)-3-methyl-N-[4-(2-sulfamoylphenyl)phenyl]-1H-pyrazole-5-carboxamide；2-(3-cyanophenyl)-5-methyl-N-[4-(2-sulfamoylphenyl)phenyl]pyrazole-3-carboxamide
• CAS: 209960-79-2
• 化学式: C₂₄H₁₉N₅O₃S
• 分子量: 457.513
• InChiKey: IFPBHAYHKREZTD-UHFFFAOYSA-N

物化性质

• 密度：
  1.36±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  33
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.04
• 拓扑面积：
  139
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  三氟乙酸 、 1-(3-cyanophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methylpyrazole 在 palladium on activated charcoal 氢气 作用下， 以 乙醇 为溶剂， 反应 18.0h， 生成 1-[3-(aminomethyl)phenyl]-N-[2'-(aminosulfonyl)-[1,1'-biphenyl]-4-yl]-3-methyl-1H-pyrazole-5-carboxamide trifluoroacetate
  参考文献：
  名称：

  Discovery of 1-[3-(Aminomethyl)phenyl]-N-[3-fluoro-2‘-(methylsulfonyl)- [1,1‘-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423), a Highly Potent, Selective, and Orally Bioavailable Inhibitor of Blood Coagulation Factor Xa

  摘要：

  Factor Xa (fXa) plays a critical role in the coagulation cascade, serving as the point of convergence of the intrinsic and extrinsic pathways. Together with nonenzymatic cofactor Va and Ca2+ on the phospholipid surface of platelets or endothelial cells, factor Xa forms the prothrombinase complex, which is responsible for the proteolysis of prothrombin to catalytically active thrombin. Thrombin, in turn, catalyzes the cleavage of fibrinogen to fibrin, thus initiating a process that ultimately leads to clot formation. Recently, we reported on a series of isoxazoline and isoxazole monobasic noncovalent inhibitors of factor Xa which show good potency in animal models of thrombosis. In this paper, we wish to report on the optimization of the heterocyclic core, which ultimately led to the discovery of a novel pyrazole SN429 (2b; fXa K-i = 13 pM). We also report on our efforts to improve the oral bioavailability and pharmacokinetic profile of this series while maintaining subnanomolar potency and in vitro selectivity. This was achieved by replacing the highly basic benzamidine P-1 with a less basic benzylamine moiety. Further optimization of the pyrazole core substitution and the biphenyl P-4 culminated in the discovery of DPC423 (17h), a highly potent, selective, and orally active factor Xa inhibitor which was chosen for clinical development.

  DOI：

  10.1021/jm000409z
• 作为产物：
  描述：

  1-(3-cyanophenyl)-N-[2'-(tert-butylaminosulfonyl) [1,1'-biphenyl]-4-yl]-3-methyl-1H-pyrazole-5-carboxamide 在 三氟乙酸 作用下， 反应 1.0h， 生成 1-(3-cyanophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methylpyrazole
  参考文献：
  名称：

  Structure-Based Design of Novel Guanidine/Benzamidine Mimics:  Potent and Orally Bioavailable Factor Xa Inhibitors as Novel Anticoagulants

  摘要：

  As part of an ongoing effort to prepare orally active factor Xa inhibitors using structure-based drug design techniques and molecular recognition principles, a systematic study has been performed on the pharmacokinetic profile resulting from replacing the benzamidine in the P1 position with less basic benzamidine mimics or neutral residues. It is demonstrated that lowering the pK(a) of the P1 ligand resulted in compounds (3-benzylamine, 15a; 1-aminoisoquinoline, 24a; 3-aminobenzisoxazole, 23a; 3-phenylcarboxamide, 22b; and 4-methoxyphenyl, 22a) with improved pharmacokinetic features mainly as a result of decreased clearance, increased volume of distribution, and enhanced oral absorption. This work resulted in a series of potent and orally bioavailable factor Xa inhibitors that ultimately led to the discovery of SQ311, 24a. SQ311, which utilizes a 1-aminoisoquinoline as the P1 ligand, inhibits factor Xa with a K-i of 0.33 nM and demonstrates both good in vivo antithrombotic efficacy and oral bioavailability.

  DOI：

  10.1021/jm020578e

文献信息

• NITROGEN CONTAINING HETEROAROMATICS AS FACTOR Xa INHIBITORS
  申请人：Bristol-Myers Squibb Pharma Company

  公开号：EP0946508B1

  公开（公告）日：2009-09-23